1. Field of the Invention
This invention relates to an injectable hydrogel that comprises a matrix based on (a) cross-linked biopolymer(s) (single-phase-type matrix) in which previously cross-linked biopolymer particles have been co-cross-linked.
This invention also relates to the process for production of injectable hydrogel.
This invention also has as its object the use of the above-mentioned hydrogel in therapeutic applications and in the dermato-cosmetic field.
2. Description of the Related Art
The use of viscoelastic products that are based on (a) cross-linked biopolymer(s) is common for separating, replacing or filling in a biological tissue or increasing the volume of said tissue or else supplementing or replacing a biological fluid.
Thus, the viscoelastic products that are based on (a) cross-linked biopolymer(s) are used in numerous therapeutic applications and in the dermato-cosmetic field.
For example, the viscoelastic products that are based on (a) cross-linked biopolymer(s) are used:                in rheumatology, as a replacement agent, a temporary supplement of the synovial fluid,        in urology/gynecology, as an agent that makes it possible to increase the volume of the sphincter or the urethra,        in ophthalmology, as an adjuvant in cataract surgery or for glaucoma treatment,        in pharmaceuticals, as a gel for releasing active substances,        in surgery, for bone reconstruction, the increase of the volume of the vocal chords, or the production of surgical tissues,        in dermato-cosmetics, for filling in wrinkles, masking scars or increasing the volume of the lips.        
From the prior art, two large families of gels that are based on biodegradable biopolymers are known: the gels called “single-phase” and the gels called “two-phase.”
Biopolymers are polymers that are present in living organisms or organisms that are synthesized by the latter; they are called biodegradable when they can be resorbed over time in the treated zone (zone into which they have been inserted or injected).
The single-phase gels, based on one or more cross-linked biodegradable biopolymers, such as sodium hyaluronate, come in the form of a single phase. These single-phase gels that are based on (a) biodegradable biopolymer(s) degrade over time, in a superficial way. This surface degradation occurs slowly, taking into account the cross-linked nature of these gels.
The two-phase gels comprise particles that consist of one or more cross-linked biopolymers (such as sodium hyaluronate), dispersed in a fluid phase, such as a physiological solution, a buffer solution, or a biopolymer-based solution. In this case, this fluid phase plays a vector role. For these two-phase gels, the degradation of the fluid phase is very quick. Injected intradermally, the half-life of this fluid phase is approximately 48 hours if it consists of non-cross-linked sodium hyaluronate. The degradation of the cross-linked particles is slow and occurs by surface degradation.
However, so as to ensure their function with effectiveness, the cross-linked biopolymer-based viscoelastic products and therefore the hydrogel of this invention should meet in particular the following requirements: to be injectable through a needle, to have a strong remanence (dwell time of the gel at the injection site), and to have a strong capacity to create volume when they are inserted into a tissue whose volume it is desired to increase.
The document FR2733426 describes a matrix that is designed to fill in wrinkles and that comprises: a biocompatible polymer, copolymerized by intercatenary bridging (cross-linking) and then transformed into microspheres, and a gel of the same polymer that may or may not be cross-linked. The microspheres can be suspended in the cross-linked gel.
The document WO00/01428 describes a process for preparation of two-phase compositions that first comprises the preparation of a continuous phase, such as a hydrogel with cross-linked hyaluronic acid. Then, the preparation of a dispersed phase in the form of particles obtained from a polymer hydrogel obtained by polymerization and cross-linking of acrylic acid and/or methacrylic acid and/or one of their derivatives is produced. Finally, these two phases—continuous phase and dispersed phase—are mixed.